Director’s Report to theNational Advisory Council

on Drug AbuseSeptember 6, 2017

Nora D. Volkow, M.D., Director

National Instituteon Drug Abuse

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Director’s Report to the National Advisory Council on Drug Abuse

Budget Update

What’s New @ HHS/NIH?

Recent NIDA Activities & Events

NIDA BUDGET(Thousands)

FY 2016 FY 2017 FY 2018Actuals Operating Plan PB

NonAIDS $754,727 $794,135 $647,674

AIDS $294,244 $276,711 $217,324

TOTAL $1,048,971 $1,070,846 $854,998

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Director’s Report to the National Advisory Council on Drug Abuse

Budget Update

What’s New @ HHS/NIH?

Recent NIDA Activities & Events

Research InitiativeNIH Next Generation NIResearH Nexcht G Ienneitiratativeion Challenge: • Too many researchers vying for limited

resources • Many highly meritorious applications go

unfunded• Particularly challenging for many early

-­‐stage and mid-­‐career investigatorsGoal: Focus support for early-­‐stage

(ESIs – within 10 years of terminal degree)and early established investigators(EEIs – within 10 years of first major NIH competing award as an ESI)

NIH hopes to support a combined additional ~400 ESIs and EEIs in FY 2017, ramping up to ~ $1.1 billion per year after five years

New NIH Definition of Clinical TrialNew NIH Definition of Clinical TrialClinical Trial: A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-­related biomedical or behavioral outcomes.

Clinical Trials need to:

Respond to a clinical trial-­specific FOA

Address additional review criteria specific for clinical trials

Register and report clinical trial in ClinicalTrials.gov

Due Dates on or after January 25,

2018 All clinical trial applications MUST be submitted to an FOA that allows clinical trials

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THE BRAIN INITIATIVE®Funds Supporting BRAIN

Scientific Areas

$-­‐

$50

$100

$150

$200

$250 M

illio

ns

Data Coordination/Informatics

Neuroethics

Training/Dissemination

Human Imaging/Modulation

Understanding Circuits

Neural Recording/Modulation

Cell/Circuit Tools

Cell Types

1. Census of Brain Cell Types (4 FOAs)2. Tools for Cells and Circuits (1 FOA)3. Technologies for Neural Recording and Modulation (3 FOAs)4. Understanding Neural Circuits (3 FOAs)5. Human Imaging and Neuromodulation (8 FOAs)6. Data Coordination (3 FOAs)7. Technology Dissemination and Training (1 FOA)8. Neuroethics (1 FOA)

* FY17 does not include multi-­‐year funds, and includes some awards that may be made in early 2018. FY

17 F

OAs

rece

ivin

g FY

17 fu

nds

A bar graph shows the funding amounts for the different FOAs supporting scientific areas of brain research, for FY 2014, FY 2015, FY 2016, and an estimate for FY 2017 funding. Gradations on the bars represent the scientific areas. The funding amounts in each year for 5 main brain science areas are as follows:

FY 2014 FY 2015 FY 2016 FY 2017 (estimate) Census of Brain Cell Types

$6,428,017 $17,854,240 $27,112,667 $46,884,472

Tools for Cells and Circuits

$12,888,647 $25,385,832 $27,112,667 $28,877,614

Technologies for Neural Recording and Modulation

$9,657,719 $25,385,832 $40,781,027 $35,333,994

Understanding Neural Circuits

$4,330,316 $19,423,226 $24,219,895 $45,607,091

Human Imaging and Neuromodulation

not shown $431,998 $45,110,569 $60,880,116

Data Coordination /Informaticss

$ 4,011,774

THE BRAIN INITIATIVE® BRAIN SFN Events

BRAIN Initiative: New Concepts and Early -­ Stage Research for Large -­ Scale Recording and Modulation in the Nervous System (R21) (RFA-­EY-­17-­002)

Posted Date: July 17, 2017;; Open Date: September 26, 2017Application Receipt Date(s): October 26, 2017

BRAIN Initiative: Research on the Ethical Implications Advancements in Neurotechnology and Brain Science (R01) (RFA-­MH-­18-­500)

Posted Date: August 25, 2017;; Open Date: November 7, 2017Application Receipt Date(s): December 7, 2017

Symposia:Exciting New Tools and Technologies Emerging From the BRAIN Initiative Chair: Joshua A. Gordon, MD, PhD

BRAIN Initiative Networking SatelliteWhen: 6:30pm-­‐9:30pm (EST), November 12, 2017

Sponsor: The BRAIN Initiative Alliance

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Director’s Report to the National Advisory Council on Drug Abuse

Budget Update

What’s New @ HHS/NIH?

Recent NIDA Activities & Events

ABCD Update

0 57 194 417 6711008

13621813

22682717

33724053

4750

0

1000

2000

3000

4000

5000

Num

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ticip

ants

ABCD Enrollmentthrough of 9/4/17

Singletons Twins Total

ABCD Study Fast Track Data https://data-­‐archive.nimh.nih.gov/abcd

Unprocessed neuroimaging data as well as basic participant demographics (age, sex), including:• High-­‐resolution structural data (3D T1 -­‐ and T2-­‐weighted

scans)• Advanced diffusion MRI (multiple b-­‐values and directions)• Resting State fMRI• Task fMRI (Monetary Incentive Delay, Stop-­‐Signal, and

Emotional N-­‐Back), along with raw E-­‐Prime task files

4819 as of today

Annual Curated Data ReleaseCurated data, including all assessment domains and computational analysis pipelines, will be released annually, starting in December 2017 with the first 4700 participants.

Fentanyl Overtakes Heroin as Leading Cause of U.S. Drug DeathJOSH KATZ © SEPT. 2, 2017Drug overdoses killed roughly 64,000 people in USA in 2016;; 22%rise over 2015.Fentanyls are changing equation: Death rate in Maryland last year outpaced that in Kentucky and Maine.

Estimate U.S. Drug Deaths in 2016

Graph from NY Times Article based on CDC MMWR Report 2017

1 Medications Development for Opioid Use Disorders and for Overdose Prevention and Reversal -­-­ June 5, 2017

2 Development of Safe, Effective, Non-­Addictive Pain Treatments -­-­ June 16, 2017

3 Understanding the Neurobiological Mechanisms of Pain -­-­ July 7, 2017

Medication Assisted Treatment (MAT)

OpioidEffect

Full Agonist(Methadone: Daily Dosing)

Partial Agonist(Buprenorphine: 3-­4X week)

Antagonist(Naltrexone: ER 1 month)

Log Dose

DECREASES:• Opioid use• Opioid-­related overdose deaths• Criminal activity• Infectious disease transmission

INCREASES• Social functioning• Retention in treatment

But MAT is highly underutilized!Relapse rates are very high!

OUD Cascade of Care in USACurrent estimatesTreatment gap90% goal

Williams AR, Nunes E, Olfson M. Health Affairs Blog, 2017

Medication Dropout in OUDTreatment completion rate higher for methadone vs. buprenorphine

74%

46%

Hser Y, et al. 2014

• After completing treatment program 50-­70% resume substance use in first year– most within 90 days

• 90% of patients require additional treatment within 4 years

• 50% patients required 3-­4 treatment admissions to sustain recovery for 1 year or more

Dennis ML and Scott CK, 2012

Extended Release Formulations

IM Injection q 4 weeks for 24 weeksMedian % Opioid-­‐Negative Urines

Placebo: N=124XR-NTX: N=126

Perc

ent o

f Wee

kly

Urin

e Te

sts

100%

80%

60%

40%

20%

0%PLACEBO XR-­‐NTX

Krupitzky et al., Lancet 2011 Apr 30;;377(9776):1506-­13.

PROBUPHINE®

Rosenthal et al., Addiction 2013;;105.

FDA approval – May 26, 2016

Opportunities for Partnership in the Development of Longer Acting Formulations and/or Drug Combinations to Improve

Treatment Compliance and Retention

Target Selection on the Basis of the Neurocircuitry of Addiction

Koob GF, Volkow ND. Neuropsychopharmacol Rev, 2010

Promising TargetsMechanisms to reduce stress-­induced drug seeking• Kappa Opioid Receptor Antagonists• OX-­1 Receptor Antagonists• NOP Receptor Agonists• α2-­Adrenergic Receptor Agonists• PDE7 InhibitorsMechanisms to reduce cue-­induced drug seeking• D3 Receptor Antagonists• OX-­1 Receptor Antagonists• 5-­HT2C Receptor Agonists• 5-­HT2A Receptor Inverse Agonists• mGluR2 Positive Allosteric Modulators• 5-­HT6 Receptor Inhibitors• PDE7 Inhibitors

Opportunities for Partnership in Sharing of Compounds and for de-­risking potential new targets for treatment of OUD

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Monoclonal Antibodies and Vaccines to Treat OUDand Prevent Overdose

Heroin vaccine validated in primate modelin 2017

First vaccine for fentanyl and fentanylanalogs reported in a mouse model in2016

Reduces drug reaching the brain

Protect high-­risk individuals againstoverdose

Bremer et al, 2017;; Bremer et al, 2016;; Janda and Treweek, 2012.

Opportunities for Partnership in Sharing of Reagents and for De-­risking Vaccines or Monoclonal Antibodies for Treatment of OUD

Medications for Overdose Reversal and Prevention

•NARCAN® Nasal Spray device

$37.50 per 4mg

Approved by FDANovember 2015

5,000

10,000

15,000

02/16 05/16 08/16 11/16 02/17

IMS

Mon

thly

Pres

crip

tions

Narcan Nasal Spray

Opioid Overdose Reversal By Narcan® Nasal Spray

Avetian GE et al., Current Medial Research and Opinion, 23 May 2017.

Stronger, longer acting formulations for extra potent opioids (e.g. fentanyl)Medications and Heroin/Fentanyl Vaccines to prevent OverdosesMedications (i.e Ampakines) and Stimulation devices to prevent respiratory depressionOD detection and autoinjectorsPost-­overdose interventions for treatment engagement

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Intravenous

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Medications Development for OUD

Key Challenges:Minimal Industry InvolvementLack of infrastructure for OUD treatment Lack of reimbursement for OUD medications is a disincentive for medication developmentAbstinence as main outcome for medication approval by FDA is a major challenge for medication development

Major Needs:Incentives to encourage private industry investment.Better surveillance and long-­term outcomes data on MAT and OD Funding

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Medications Development for OUD

Next Steps:PPP * Dr. Collins will describe thisExpand Clinical Network to rapidly deploy clinical trials and for epidemiological studies Engage CMS to address reimbursementEngage FDA for alternative outcomes for medicationapprovalExplore mechanisms to expedite NIH review of grantproposals

Later this morning…NIH Director Dr. Francis Collins will discuss the public-­private partnership effort that NIH will be launching to address the opioid crisis

Priority AreasPrevention Research(Children & Adolescents)

genetics/epigeneticsdevelopmentenvironmentco-­morbidity

Treatment Interventions(New Targets & New Strategies)

Rates of U.S. Adults > 18 and Older Reporting Pain, 2015

CDC and NCHS, 2015

9.9

27.6

13.9

20.9

30.4

17.4

05101520253035

Severe headache or migraine

Low back pain

Neck pain

MenWomen

Women suffer more pain in many categories and are Prescribed more Opioids

0

20000000

40000000

60000000

80000000

100000000

120000000

140000000

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Males Females

Opioid Prescriptions U.S. Retail Pharmacies, 2002-­‐2013

Source: IMS Health, National Prescription Audit

Num

ber o

f Prescrip

tion

Cicero TJ et al., JAMA Psychiatry 2014.

The Changing Face of Heroin Use in the US

493

3139 3095

222

2007

2986

0

500

1000

1500

2000

2500

3000

3500

4000

15-­24 years 25-­44 years 45-­64 years

MaleFemale

Num

ber

Rudd RA et al., MMWR Morb Mortal Wkly Rep 2016

Deaths Involving Natural and Semi-­Synthetic Opioids

Neurobiology of Pain

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Gender Differences in Kappa Opioid Receptor Availability

Males

Females

Males had higher K opioid receptor availability than females presumably from increased dynorphin.

Could this help explain gender differences in pain catastrophizing??

Vijay et al., Am J Nucl Med Mol Imaging. 2016 6(4):205-­214.

New NIDA FOAs

Development of a Device to Objectively Measure Pain (R43/R44) (RFA-­DA-­18-­012);; (R41/R42) (RFA-­DA-­18-­013)

Posted Date: July 12, 2017;; Open Date: November 5, 2017;;Application Due Date(s): December 5, 2017

The goal of this RFA is to encourage Small Business Concerns (SBCs) to develop a tool to objectively measure pain for research or clinical purposes.

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Priority AreasPrevention Research(Children & Adolescents)

genetics/epigeneticsdevelopmentenvironmentco-­morbidity

Treatment Interventions(New Targets & New Strategies)

HIV and DrugsPreventionTreatment

New NIDA FOAsHIV-­Associated Neuropathic Pain and Opioid Interaction (R01) (RFA-­DA-­18-­015)

Posted Date: August 3, 2017;; Open Date: November 18, 2017;;Application Due Date(s): December 18, 2017

HIV/HCV Co-­Infections in Substance Abusers (R01) (PAS-­17-­311)Posted Date: June 13, 2017;; Open Date: August 7, 2017;;

Application Due Date(s): September 7, 2017 & January 7, 2018

(a) impact of substance abuse on HIV, HIV/HCV co-­infection disease progression, (b) interactions between HIV and HCV, (c) hepatic and non-­hepatic co-­morbidities associated with HIV/HCV co-­infections in SUD, (d) effectiveness of interferon-­free direct acting antivirals (DAAs) to treat HIV/HCV co-­infections in SUDs.

2017 Intel International Science and Engineering Fair Addiction Science Awards

Anusha Zaman from Baton Rouge Magnet High School, LouisianaEpigenetic and Biotransformation Effects of Hookah Smoke Extract on Human Oral Keratinocytes

Nkima Stephenson from Rockdale Magnet School for Science and Technology in Conyers, Georgia,Data Analysis of the Epigenetics of Drug and Alcohol Dependence

Kashfia Rahman from Brookings High School in Brookings, South DakotaDynamics of Habituation: A Neural Study of the Effects of Repeated Exposures to Risky Behaviors on Cognitive Control and Emotional Responses in the Adolescent Brain

1st 2nd 3rd

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Session I. Understanding the Role of Astrocytes in Nervous System FunctionJacob P. Waletzky Memorial Award Lecture Joint NIDA-­NIAAA Early Career Investigator Showcase [ECIS] Session II. Social Stressors, Immune Response and Substance Use DisordersSession III. Novel Approaches for Translational Research and Drug Discovery